rs137854613
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000335.5(SCN5A):c.4864C>T(p.Arg1622*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000335.5 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.4867C>T | p.Arg1623* | stop_gained | Exon 28 of 28 | 5 | NM_001099404.2 | ENSP00000410257.1 | ||
SCN5A | ENST00000423572.7 | c.4864C>T | p.Arg1622* | stop_gained | Exon 28 of 28 | 1 | NM_000335.5 | ENSP00000398266.2 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 0AN: 152030Hom.: 0 Cov.: 31 FAILED QC
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461728Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2AN XY: 727138
GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 152030Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74272
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation, as the last 394 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Published functional studies demonstrate that R1623X results in no inward sodium current, indicating this variant causes a non-functional sodium channel (PMID: 16325048); This variant is associated with the following publications: (PMID: 19027780, 18436145, 17368591, 30147658, 20539757, 20129283, 28341781, 28552050, 15840483, 26187847, 30203441, 14523039, 31043699, 33221895, 31402444, 32600061, 33087929, 33131149, 28069705, 29574140, 16325048) -
- -
This sequence change creates a premature translational stop signal (p.Arg1623*) in the SCN5A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 394 amino acid(s) of the SCN5A protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with cardiac conditions including sick sinus syndrome, heart block, bradycardia and Brugada syndrome (PMID: 14523039, 16325048, 29574140). ClinVar contains an entry for this variant (Variation ID: 9374). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects SCN5A function (PMID: 14523039, 16325048, 20539757). This variant disrupts a region of the SCN5A protein in which other variant(s) (p.Arg1629*) have been determined to be pathogenic (PMID: 18361072, 20129283, 25829473). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Brugada syndrome Pathogenic:2
The p.Arg1623X variant in SCN5A has been reported in 2 heterozygous individuals with Brugada syndrome (Todd 2005, Mikayama 2005), 1 compound heterozygous individual with sick sinus syndrome (Benson 2003), and one heterozygous individual with ARVC who also carried a heterozygous pathogenic splice variant in PKP2 (te Riele 2017). The p.Arg1623X variant segregated with Brugada syndrome in one family member and with heart block in 3 family members (Benson 2003, Todd 2005). This variant was also absent from large population studies. This variant has also been reported in ClinVar (Variation ID 9374). This nonsense variant leads to a premature termination codon at position 1623. This alteration occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. While the effect on the protein is unknown, in vitro functional studies provide some evidence that the p.Arg1623X variant causes a loss of function (Benson 2003, Makiyama 2005, Gui 2010). Heterozygous loss of function variants of the SCN5A gene have been previously reported for DCM (Olson 2005), Brugada syndrome (Kapplinger 2010), ventricular fibrillation (Chen 1998), and atrioventricular block and cardiac conduction defects (Baruteau 2012). In summary, this variant meets criteria to be classified as pathogenic for SCN5A-related disorders in an autosomal dominant manner based upon segregation studies, absence from controls, functional evidence, and impact to the protein. -
This variant changes 1 nucleotide in exon 28 of the SCN5A gene, creating a premature translation stop signal in the last exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein with disrupted transmembrane domain DIV (a.a. 1524-1772) and C-terminal region (a.a. 1773-2016). Functional studies have shown that this variant results in the loss of detectable inward sodium current (PMID: 16325048, 20539757). This variant has been reported in at least four unrelated individuals affected with Brugada syndrome (PMID: 15840483, 16325048, 28341781, 33221895) and in another two individuals suspected of having Brugada syndrome (PMID: 20129283). This variant has also been reported in an individual affected with congenital sick sinus syndrome (PMID: 14523039), in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 28069705), and in a pediatric proband affected with sudden cardiac arrest and death (PMID: 26187847). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Multiple truncation variants occurring downstream of this variant are known to be disease-causing (ClinVar variation ID: 1070823, 201573), suggesting that the impacted region is critical for SCN5A protein function. Loss of function is a known mechanism of disease for the SCN5A gene. Based on the available evidence, this variant is classified as Pathogenic. -
Cardiac arrhythmia Pathogenic:2
This variant changes 1 nucleotide in exon 28 of the SCN5A gene, creating a premature translation stop signal in the last exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein with disrupted transmembrane domain DIV (a.a. 1524-1772) and C-terminal region (a.a. 1773-2016). Functional studies have shown that this variant results in the loss of detectable inward sodium current (PMID: 16325048, 20539757). This variant has been reported in at least four unrelated individuals affected with Brugada syndrome (PMID: 15840483, 16325048, 28341781, 33221895) and in another two individuals suspected of having Brugada syndrome (PMID: 20129283). This variant has also been reported in an individual affected with congenital sick sinus syndrome (PMID: 14523039), in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 28069705), and in a pediatric proband affected with sudden cardiac arrest and death (PMID: 26187847). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Multiple truncation variants occurring downstream of this variant are known to be disease-causing (ClinVar variation ID: 1070823, 201573), suggesting that the impacted region is critical for SCN5A protein function. Loss of function is a known mechanism of disease for the SCN5A gene. Based on the available evidence, this variant is classified as Pathogenic. -
Variant summary: SCN5A c.4867C>T (p.Arg1623X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 4.1e-06 in 1461728 control chromosomes (gnomAD v4.1). c.4867C>T has been reported in the literature in multiple individuals affected with cardiac phenotypes including sick sinus syndrome, first-degree heart block, or Brugada syndrome (e.g. Benseon_2003, Ciconte_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 14523039, 33221895). ClinVar contains an entry for this variant (Variation ID: 9374). Based on the evidence outlined above, the variant was classified as pathogenic. -
SCN5A-related disorder Pathogenic:1
The SCN5A c.4867C>T (p.Arg1623Ter) variant, also referred to as c.4864C>T (p.Arg1622Ter), is a nonsense variant that results in the substitution of arginine at amino acid position 1623 with a stop codon. This variant occurs in the last exon of the gene and may escape nonsense-mediated mRNA decay. The c.4867C>T variant has been reported in a heterozygous state in at least five individuals, including four with Brugada syndrome (BrS) and one individual with left ventricular noncompaction, ventricular tachycardia, and prolonged QT (PMID: 16325048; PMID: 15840483; PMID: 32600061; PMID: 33221895). One of the individuals with BrS was also noted to have a brother who carried the variant and presented with features suggestive of BrS (PMID: 15840483). Two additional individuals have been reported with either confirmed or possible BrS (PMID: 20129283) and the variant has also been reported in a compound heterozygous state in an individual with sick sinus syndrome (PMID: 14523039). Three family members of the individual with sick sinus syndrome who carried the variant were not identified as affected, but were noted to have first-degree heart block (PMID: 14523039). The c.4867C>T variant was not detected in 1410 control individuals (PMID: 14523039; PMID: 20129283) and at least 150 additional control chromosomes. This variant failed filters in the Genome Aggregation Database version 2.1.1 and version 3.1.2; therefore, this information cannot be reliably used. Three patch clamp studies in HEK293 cells overexpressing the c.4867C>T variant demonstrated no Na+ current detection compared to wild type (PMID: 14523039; PMID: 16325048; PMID: 20539757). Similar results of no Na+ current detection were obtained when Xenopus oocytes were injected with variant cRNA when compared to wild type. A cell surface biotinylation experiment using HEK293 cells transfected with the c.4867C>T variant showed very small fractions at the plasma membrane suggesting trafficking deficiency (PMID: 20539757). Based on the available evidence, the c.4867C>T (p.Arg1623Ter) variant is classified as pathogenic for SCN5A-related disorders. -
SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1 Pathogenic:1
- -
Sick sinus syndrome 1 Pathogenic:1
- -
Cardiovascular phenotype Pathogenic:1
The p.R1623* pathogenic mutation (also known as c.4867C>T), located in coding exon 27 of the SCN5A gene, results from a C to T substitution at nucleotide position 4867. This changes the amino acid from an arginine to a stop codon within coding exon 27. This alteration was first reported in a pediatric patient with sick sinus syndrome who also carried a second missense alteration in SCN5A. The p.R1623* mutation was also seen in the patient's mother, maternal aunt and maternal grandmother who were all found to have heart block (Benson DW et al. J. Clin. Invest., 2003 Oct;112:1019-28). This alteration has also been reported in subjects with clinical Brugada syndrome (Todd SJ et al. Heart Rhythm, 2005 May;2:540-3; Makiyama T et al. J. Am. Coll. Cardiol., 2005 Dec;46:2100-6) and has been seen in a subject with arrhythmogenic right ventricular cardiomyopathy (ARVC) who also harbored a splicing alteration in PKP2 (Te Riele AS et al. Cardiovasc. Res., 2017 Jan;113:102-111). Functional studies support that this alteration results in a non-functional sodium channel (Benson DW et al. J. Clin. Invest., 2003 Oct;112:1019-28; Makiyama T et al. J. Am. Coll. Cardiol., 2005 Dec;46:2100-6; Gui J et al. PLoS ONE, 2010 Jun;5:e10985). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -
Long QT syndrome 3 Pathogenic:1
- -
Familial isolated arrhythmogenic right ventricular dysplasia Pathogenic:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at